Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.

The precise neuromodulatory mechanisms underlying consciousness and its disorders, despite growing evidence in both animals and humans, remain poorly understood at the subcortical level. The basal ganglia, a key component of the cortico-basal ganglia-thalamo-cortical loop, are known to play a crucial role in mediating consciousness and behavioural responsiveness to the environment. Here, we aimed to present a comprehensive mapping of the distinct contributions of basal ganglia nuclei and their associated neurotransmitter systems in pharmacologically induced and pathological loss of responsiveness. We used functional MRI to provide a systematic investigation of 9 major nuclei (putamen, caudate, nucleus accumbens, globus pallidus external, globus pallidus internal, substantia nigra pars compacta, substantia nigra pars reticulata, ventral pallidus, and subthalamic nucleus) and their functional relationship with 19 major neurotransmitter systems in loss of responsiveness, in both healthy volunteers under propofol anaesthesia (n = 16) and patients with disorders of consciousness (DOC) (i.e. minimally conscious, unresponsive wakefulness syndrome) (n = 22). We found that in pharmacologically-induced loss of responsiveness, the functional connectivity changes of the putamen (Pu) correlated with the norepinephrine transporter (NET), and the globus pallidus external (GPe) with the serotonin transporter (5-HTT) and vesicular acetylcholine transporter (VAChT); additionally, altered connectivity in the ventral pallidum (VeP) was associated with the norepinephrine transporter (NET). In contrast, with pathological-induced loss of responsiveness, we found that connectivity changes of the caudate were associated with the serotonin transporter (5-HTT), dopamine transporter (DAT), and GABAA receptor, and connectivity changes of the substantia nigra pars compacta (SNc) were associated with the cannabinoid (CB1) receptor. Finally, we report that among all basal ganglia nuclei, a key dopamine-rich area of the basal ganglia-the substantia nigra-was found to have the largest DOC subgroup difference in functional connectivity, following stratification based on mental-imagery task responsiveness. Critically, we provide evidence that pharmacological and pathological loss of responsiveness involve distinct neurotransmitter system contributions across individual basal ganglia nuclei, offering a novel framework for targeted therapeutic interventions in patients with disorders of consciousness.

Corticobasal degeneration (CBD) is a late onset progressive neurodegenerative condition of the 4-repeat-tauopathy-type, classically presenting with asymmetrical rigidity, dystonia and myoclonus. In the most recent diagnostic criteria, Armstrong and colleagues (2013) described four clinical phenotypes associated with this pathology, including corticobasal syndrome (CBS), through a large retrospective analysis of published cases and confirmed brain bank cases of CBD. However, predicting CBD pathology remains challenging. With the advent of disease-modifying therapies, it has become particularly important to distinguish Alzheimer's disease pathology from other underlying pathologies. We therefore combined two prospectively recruited cohorts of patients with CBS and analysed their key demographic, clinical and biomarker features. We included a separate cohort from UK brain banks who were diagnosed with CBS in life. We divided patients into three groups: CBS-Alzheimer's (CBS-AD), CBS-non-Alzheimer's (CBS-non-AD) and CBS-indeterminate (CBS-IDT) based on biomarkers and pathology, comparing clinical features, regional volumetric MRI measures and Nucleic Acid-Linked Immuno-Sandwich Assay with detection by next generation sequencing (NULISAseq) blood protein levels between groups. We performed additional analyses of pathologically verified cases. We included 397 participants, of which 57.7% were female. The mean age at symptom onset was 65.9 years. AD biomarkers and pathology permitted classifying 47 (11.8%) of the cases as CBS-AD, 134 (33.8%) as CBS-non-AD and 216 (54.4%) as CBS-IDT. Patients with CBS-AD had a younger age at onset (61.8 years vs 66.1 years, P < 0.01 and less severe motor deficits (non-significantly lower scores on MDS-UPDRS and PSPRS) and more severe cognitive impairment (non-significantly lower scores on MoCA). Patients with CBS-AD had higher rates of cortical sensory impairment (P = 0.087) and lower rates of limb dystonia (P < 0.01) and falls (P < 0.01) compared to the CBS-non-AD group. Volumetric MRI analysis revealed smaller parietal lobe volumes in CBS-AD (P = 0.01). The most common pathological diagnoses were PSP, CBD and AD. Limb dystonia was more common in people with CBD and PSP pathology (P = 0.077). Falls, impaired verbal fluency and impaired vertical saccades were confirmed as more common in PSP (P = 0.046, P = 0.040, P = 0.012, respectively). In summary, younger onset, less parkinsonism and more cognitive and cortical sensory impairment, along with reduced MRI parietal volumes point to CBS-AD, while limb dystonia, falls and worse verbal fluency relate to CBS-non-AD. Clinical, imaging and blood-biomarkers in can augment the Armstrong criteria in predicting the underlying pathology of corticobasal syndromes.

Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.

Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.

Epilepsy care is often guided by incomplete snapshots: patient-reported seizures, intermittent drug levels and medication histories that may not reflect current exposure. Between these snapshots, clinicians have little objective information about how the brain is responding to antiseizure medication. In this study, we tested whether intracranial EEG synchrony, a measure of coordinated neural activity across intracranial electrodes, tracks antiseizure medication load in patients with drug-resistant epilepsy. We retrospectively studied 80 consecutive patients with drug-resistant epilepsy who underwent presurgical intracranial EEG monitoring at the Hospital of the University of Pennsylvania. Antiseizure medication load was estimated continuously from medication administration records using a validated pharmacokinetic model. Synchrony was computed from intracranial EEG using the Kuramoto order parameter. We first compared synchrony within the same patient during high and low medication exposure. We then tested the continuous association between synchrony and medication load across the epilepsy monitoring unit admission, adjusting for time since admission, seizure timing, wakefulness, time of day and interictal spike rate. Analyses accounted for repeated measurements within patients and tested robustness to temporal structure in the recordings. We also assessed whether synchrony dynamics were preserved when fewer electrodes were sampled. Forty-five patients had sufficient high- and low-exposure data after peri-ictal exclusion. Synchrony was higher during low medication exposure in 32 of 45 patients, corresponding to a median 7.4% increase and a median paired difference of 0.0082 on the 0-1 synchrony scale (sign test P = 0.007; Wilcoxon P < 0.001). In the continuous analysis of 67 patients and 23,402 repeated 10-minute observations, higher synchrony was associated with lower medication load (β = -0.153, 95% confidence interval -0.293 to -0.012, P = 0.033); interictal spike rate was not independently associated with medication load. The inverse association remained evident in circular-shift, temporally binned and likelihood-based sensitivity analyses. Relative synchrony dynamics were preserved under electrode subsampling, with a median correlation of 0.85 with full-array synchrony at 40% sampling. These findings support synchrony as a candidate continuous physiological readout of antiseizure medication load in patients with drug-resistant epilepsy. By linking medication exposure to a measurable brain-network state, synchrony may help move epilepsy monitoring beyond seizure counting alone and toward continuous assessment of how the brain is responding to treatment.

Severe and enduring psychiatric illness is a major cause of long-term disability and reduced life expectancy. Within this group, treatment-resistant depression (TRD) remains a substantial therapeutic challenge. Ablative neurosurgery, defined here as anterior cingulotomy (ACING) which creates bilateral lesions in the dorsal cingulum bundle, and anterior capsulotomy (ACAPS) which creates bilateral lesions in the anterior thalamic radiation, can produce sustained clinical response in carefully selected patients, but the underlying mechanisms are not well understood. Here, we examined whether prior neurosurgical treatment is associated with differences in behavioural and neural processes implicated in TRD. Sixty-two participants completed a probabilistic reward-loss learning task during event-related fMRI: patients with a history of neurosurgical treatment, non-surgical TRD patients, and healthy controls. Behaviour was modelled using hierarchical Bayesian reinforcement learning drift-diffusion models, enabling decomposition of value learning, prediction-error updating, evidence accumulation, and non-decision processes. TRD was associated with impaired value discrimination, blunted reward prediction-error signals, increased loss-related responses, and slowed response dynamics. Behavioural accuracy and learning were preserved across groups, but reaction time analyses revealed graded slowing. Relative to non-surgical TRD, the surgical group showed differences in value-related processing but not in response slowing. Within the surgical cohort, clinical responders showed more efficient evidence accumulation and more normal value representation, whereas non-responders exhibited persistent abnormalities in reward valuation and a 'pessimistic' prediction-error profile. Neuroimaging analyses showed corresponding differences in reward- and loss-related circuits. Responders demonstrated increased reward prediction-error signalling in dorsal anterior cingulate cortex and enhanced reward-value signals in lateral orbitofrontal cortex, whereas non-responders showed persistent blunting of subcortical reward prediction-error responses associated with greater symptom severity. These findings suggest that clinical improvement following neurosurgical treatment is associated with relative normalisation of valuation-related neurophysiology, rather than changes in response slowing. More broadly, they highlight valuation processes as a key component of severe TRD and a potential target for future therapeutic interventions.